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Stress-Responsive Regulation of Mitochondria Through the ER

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Stress-Responsive Regulation of Mitochondria Through the ER TEM-969; No. of Pages 10 Review Stress-responsive regulation of mitochondria through the ER unfolded protein response T. Kelly Rainbolt, Jaclyn M. Saunders, and R. Luke Wiseman Department of Molecular and Experimental Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA The endoplasmic reticulum (ER) and mitochondria form function is sensitive to pathologic insults that induce ER physical interactions involved in the regulation of bio- stress (defined by the increased accumulation of misfolded logic functions including mitochondrial bioenergetics proteins within the ER lumen). ER stress can be transmit- and apoptotic signaling. To coordinate these functions ted to mitochondria by alterations in the transfer of me- 2+ during stress, cells must coregulate ER and mitochon- tabolites such as Ca or by stress-responsive signaling dria through stress-responsive signaling pathways such pathways, directly influencing mitochondrial functions. as the ER unfolded protein response (UPR). Although the Depending on the extent of cellular stress, the stress UPR is traditionally viewed as a signaling pathway re- signaling from the ER to mitochondria can result in pro- sponsible for regulating ER proteostasis, it is becoming survival or proapoptotic adaptations in mitochondrial increasingly clear that the protein kinase RNA (PKR)-like function. endoplasmic reticulum kinase (PERK) signaling pathway During the early adaptive phase of ER stress, ER– 2+ within the UPR can also regulate mitochondria proteos- mitochondrial contacts increase, promoting Ca transfer 2+ tasis and function in response to pathologic insults that between these organelles [4]. This increase in Ca flux into induce ER stress. Here, we discuss the contributions of mitochondria stimulates mitochondrial metabolism 2+ PERK in coordinating ER–mitochondrial activities and through the activity of Ca -regulated dehydrogenases describe the mechanisms by which PERK adapts mito- involved in the tricarboxylic acid (TCA) cycle. The in- chondrial proteostasis and function in response to ER creased activity of these dehydrogenases promotes mito- stress. chondrial respiratory chain activity, resulting in a transient increase in mitochondrial ATP synthesis during ER stress impacts mitochondrial function through the initial phase of ER stress. This surge in bioenergetic interorganellar signaling capacity increases the available energetic resources to The traditional view of ER and mitochondria as discreet mount an adaptive response and alleviate ER stress. Al- intracellular organelles has been profoundly altered in ternatively, chronic exposure to ER stress negatively recent years. Unlike the well-defined organelles described impacts cellular metabolism by reducing mitochondrial in cell biology textbooks, the ER and mitochondria are respiration and decreasing cellular ATP levels [4,5]. This 2+ highly dynamic and undergo continuous structural and has been shown to lead to depletion of Ca stores in the ER 2+ spatial reorganization in response to specific cellular and increased Ca within mitochondria ([6,7] and dis- signals. An interesting aspect of these organelles is that cussed below). Ultimately, this signaling results in mito- they form physical ER–mitochondrial contacts (reviewed chondrial fragmentation and the opening of the in [1–3]). These contacts facilitate the transfer of metab- mitochondrial permeability transition pore (MPTP), which 2+ olites, including lipids and Ca , between the ER and initiates intrinsic apoptotic signaling and programmed cell mitochondria that are involved in the regulation of biologic death. Varying levels of ER stress in multiple cell types functions including lipid homeostasis, mitochondrial me- have also been reported to impact other mitochondrial tabolism, and the regulation of apoptotic signaling (Box 1). functions including mitochondrial DNA (mtDNA) biogene- Thus, ER–mitochondrial contacts serve as a platform for sis [8], the transcription of respiratory chain subunits [5], interorganellar communication, essential for the coordina- and increases in mitochondrial-derived reactive oxygen tion of cellular function. species (ROS) [5,9,10], further reflecting the capacity for A consequence of the physical and functional interaction ER stress to influence mitochondrial function. between ER and mitochondria is that mitochondria Many metabolic diseases including nonalcoholic fatty liver disease, type 2 diabetes (T2D), and obesity are asso- Corresponding author: Wiseman, R.L. ([email protected]). ciated with unresolved ER stress, suggesting that mito- Keywords: mitochondrial proteostasis; mitochondrial quality control; chondrial dysfunction in these diseases may be unfolded protein response (UPR); PERK; eIF2a phosphorylation. dysregulated through mechanisms involving ER stress- 1043-2760/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2014.06.007 dependent alterations in ER–mitochondria communica- tion [11,12]. For example, stress-dependent alterations Trends in Endocrinology and Metabolism xx (2014) 1–10 1 TEM-969; No. of Pages 10 Review Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x Box 1. Metabolite transfer through ER–mitochondrial contacts ER and mitochondria form tight physical junctions stabilized by tethering import complex components [93–96]. The synthesis of CL involves the complexes anchored in the ER and mitochondrial outer membrane transfer of ER-derived phosphatidic acid to the mitochondrial inner (reviewed in [1–3]). In higher eukaryotes, these tethers are mediated by membrane followed by the action of a cascade of mitochondrial interactions between ER-localized MFN2 with MFN2 and MFN1 in the enzymes including cardiolipin synthase (CLS). Thus, maintaining ER– mitochondrial outer membrane. These tight interactions facilitate the mitochondrial contacts is critical for the proper synthesis of essential transfer of metabolites between the two organelles (Figure I). lipids, such as CL, and for maintaining normal mitochondrial function 2+ Transfer of Ca between the ER and mitochondria is a major and cellular physiology. function for ER–mitochondrial contacts and is carried out through the IP3R and VDAC transporters localized to the ER and mitochondria outer membranes, respectively (see [1–3]). These channels form a tight interaction stabilized by the cytosolic isoform of the mitochon- 2+ Mitochondria ER drial HSP70 chaperone HSPA9/GRP75/mortalin. Ca is imported into the mitochondrial matrix through the high-capacity, low-affinity 2+ mitochondrial Ca uniporter (MCU). The close physical proximity 2+ between these various Ca transporters at ER–mitochondrial con- 2+ tacts increases local Ca concentration to levels sufficient to drive MFN2 MFN2 import through MCU into the mitochondrial matrix. 2+ Flux of Ca through the ER–mitochondrial contacts is highly regulated by accessory proteins both at the ER and mitochondria MICU1 Sig1R membranes [1–3,6]. ER-localized phosphofurin acidic cluster sorting HSPA9 IP3R protein 2 (PACS2) recruits the chaperone calnexin to the ER luminal MCU VDAC Ca2+ face of MAMs to mediate their formation and stability. The ER Sigma- IP3R 1 receptor stabilizes IP3R and promotes protective ER to mitochondria HSPA9 2+ 2+ MCUR1 Ca exchange in response to ER Ca depletion. Alternatively, MCU regulators including MICU1 and MCUR1 have also been identified to 2+ 2+ PACS2 CNX influence ER–mitochondria Ca transfer and Ca -regulated mito- 2+ chondrial activities [1–3,6]. ER–mitochondrial Ca transfer is also influenced by a truncated isoform of SERCA (S1T) localized to MAMs PERK 2+ 2+ that can promote ER Ca leakage and mitochondria Ca overload associated with cellular death [1–3]. These regulators provide a 2+ MFN1 MFN2 significant level of control over ER–mitochondrial Ca transfer, reflecting the importance of this process in cellular physiology. 2+ IM OM Apart from Ca , other metabolites including lipids are also transferred between the ER and mitochondria through ER–mitochon- TRENDS in Endocrinology & Metabolism drial contacts [1–3]. Lipid biosynthesis enzymes involved in the Figure I. Illustration of the components and interactions of proteins localized to synthesis of phospholipids, cholesterol metabolites, and sphingolipids ER–mitochondrial contacts. The colored proteins represent core components of localize to the ER and mitochondrial membranes. Lipid transfer ER–mitochondrial contacts required for organelle tethering (MFN2 and MFN1) or between the ER and mitochondria is required for the biosynthesis of 2+ Ca transfer between these organelles (IP3R, VDAC, MCU, and HSPA9). The these critical metabolites, including cardiolipin (CL). CL has been shown 2+ white proteins are regulatory factors that influence the Ca signaling through to have a variety of essential functions in the mitochondria including ER–mitochondrial contacts. Abbreviations: ER, endoplasmic reticulum; MFN, maintaining membrane curvature at cristae tips and providing Mitofusin; IP3R, inositol trisphosphate receptor; VDAC, voltage-dependent anion- 2+ structural integrity to both electron transport chain and mitochondrial selective channel; MCU, mitochondrial Ca uniporter. 2+ in ER–mitochondrial Ca transfer has been proposed to familial Alzheimer’s disease is associated with mutations contribute to the pathophysiology of T2D where increased in presenilins 1 and 2 (PS1 and PS2), which are involved in cytosolic calcium leads to aberrant insulin signaling in the the generation of the toxic Amyloid
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